TRP (transient receptor potential) channels are non-selective cation channels that are activated by a variety of physical (e.g., temperature, osmolarity, or mechanical) and chemical stimuli. A subset of the TRP channel superfamily is thermoresponsive, each channel being activated over a discrete temperature range, cumulatively spanning from noxious cold to noxious heat. TRPM8 belongs to the melastatin subgroup of the TRP channel superfamily TRPM8 is sensitive to cold temperature and menthol, and therefore also called as cold menthol receptor-1 (CMR-1). TRPM8 is known to be stimulated by cold temperatures (8 to 28° C.) as well as by chemical substances such as menthol and icilin (e.g., Nonpatent Document 1).
TRPM8 is mainly located on primary nociceptive neurons (A-δ and C-fibers) and is also modulated by inflammation-mediated second messengers (e.g., Nonpatent Documents 2 and 3). The location of TRPM8 on both A-δ and C-fibers may provide a basis for abnormal cold sensitivity in pathologic conditions wherein these neurons are altered, resulting in pain, often of a burning nature. TRPM8 immunostaining in primary afferents was increased in rats with chronic constriction injury (CCI), a neuropathic pain model manifesting cold allodynia in hindlimbs (e.g., Nonpatent Document 4). The expression of TRPM8 in primary afferents was increased in oxaliplatin-induced cold allodynia model in mice (e.g., Nonpatent Document 5).
Cold intolerance and paradoxical burning sensations induced by chemical substances or thermal cooling are closely parallel symptoms seen in a wide range of clinical disorders and thus provide a strong rationale for the development on TRPM8 modulators as novel antihyperalgesic or antiallodynic agents. TRPM8 is also known to be expressed in the brain, lung, bladder, gastrointestinal tract, blood vessels, prostate and immune cells, thereby providing the possibility for therapeutic modulation in a variety of maladies.
N-Benzothiophenylsulfonamide compounds (e.g., Patent Document 1), N-benzimidazolylsulfonamide compounds (e.g., Patent Document 2), N-phenylsulfonamide compounds, and N-pyridylsulfonamide compounds (e.g., Patent Document 3), etc. have been known as a TRPM8 modulator. However, it has never been reported that a compound having a structure in which isoquinolyl binds to a sulfonylamino group has a TRPM8 antagonistic activity.